This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To generate strong cytotoxic T lymphocytes (CTL) responses, in the absence of other immune responses, using several different vaccine approaches. PROGRESS All HIV vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly-reactive neutralizing antibodies. To explore the extent to which vaccine- induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, in 2007, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T cell responses against 11-34 epitopes. In June 2008, we began to challenge the vaccinees and eight na[unreadable]ve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical human HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both peak (1.9 log reduction p0.03) and at set point (3.3 log reduction p0.003) than those of control na[unreadable]ve animals. Six of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 vRNA copy Eq/ml and to less than 100 vRNA copy Eq/ml in the chronic phase. Vaccinees are more than two years post infection and still have viral loads below levels of detection. Significant differences are present between vaccinees and controls for time of death post infection due to SAIDS, although this data is still preliminary. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T cell based vaccines may have greater potential than previously appreciated. We published a paper in 2010 describing a correlation between the breadth of immune responses in Vif and, to a lesser extent, Gag that are protective. This research uses WNPRC Immunology and Virology Services (tetramers, flow cytometry instruments, Elispots) and WNPRC Genetics Services (MHC typing). PUBLICATION: Martins MA, Wilson NA, Reed JS, Ahn CD, Klimentidis YC, Allison DB, Watkins DI. T-cell correlates of vaccine efficacy after a heterologous simian immunodeficiency virus challenge. J Virol. 2010 May;84(9):4352-65. Epub 2010 Feb 17. PubMed PMID: 20164222;PMID: 20164222, PMCID: PMC2863752.